EP2884976B1 - Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl comme inhibiteurs de ror-gamma-t et leur utilisation - Google Patents

Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl comme inhibiteurs de ror-gamma-t et leur utilisation Download PDF

Info

Publication number
EP2884976B1
EP2884976B1 EP13829099.4A EP13829099A EP2884976B1 EP 2884976 B1 EP2884976 B1 EP 2884976B1 EP 13829099 A EP13829099 A EP 13829099A EP 2884976 B1 EP2884976 B1 EP 2884976B1
Authority
EP
European Patent Office
Prior art keywords
chloro
trifluoromethyl
indazol
benzoyl
cyclohex
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP13829099.4A
Other languages
German (de)
English (en)
Other versions
EP2884976A2 (fr
EP2884976A4 (fr
Inventor
Kenneth Jay BARR
John Maclean
Hongjun Zhang
Richard Thomas Beresis
Dongshan Zhang
Brian Andresen
Neville Anthony
Blair LAPOINTE
Nunzio Sciammetta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme LLC
Priority to SI201331578T priority Critical patent/SI2884976T1/sl
Priority to RSP20191289 priority patent/RS59364B1/sr
Priority to PL13829099T priority patent/PL2884976T3/pl
Priority to MEP-2019-276A priority patent/ME03579B/fr
Publication of EP2884976A2 publication Critical patent/EP2884976A2/fr
Publication of EP2884976A4 publication Critical patent/EP2884976A4/fr
Application granted granted Critical
Publication of EP2884976B1 publication Critical patent/EP2884976B1/fr
Priority to HRP20191654 priority patent/HRP20191654T1/hr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • T helper cells Upon activation by antigen-presenting cells naive T helper cells undergo clonal expansion and will ultimately differentiate in cytokine secreting effector T cells, such as Th1 and Th2 subtypes.
  • cytokine secreting effector T cells such as Th1 and Th2 subtypes.
  • a third and distinct effector subset has been identified, which plays a key role in providing immunity to bacteria and fungi at mucosal surfaces ( Kastelein et al., Annu. Rev. Immunol. 25: 221-242, 2007 ).
  • This effector T helper cell subset can be distinguished based on its ability to produce large quantities of IL-17/F, IL-21 and IL-22, and is named Th17 ( Miossec et al., New Eng. J. Med. 2361: 888-898, 2009 ).
  • Th1 and Th2 effector cells express Tbet and GATA3, respectively.
  • a Thymocyte/T cell specific variant of Retinoic Acid Receptor-related Orphan Receptor (ROR), RORgammaT is highly expressed in Th17 cells ( He et al., Immunity 9: 797-806, 1998 ).
  • RORgammaT belongs to the nuclear hormone receptor superfamily ( Hirose et al., Biochem. Biophys. Res. Comm. 205: 1976-1983, 1994 ).
  • RORgammaT is a truncated form of RORgamma, lacking the first N-terminal 21 amino acids and is, in contrast to RORgamma which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle), exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers ( Sun et al., Science 288: 2369-2372, 2000 ; Eberl et al., Nat Immunol. 5: 64-73, 2004 ).
  • RORgammaT was shown to play a crucial role in non-Th17 lymphoid cells.
  • RORgammaT was critically important in innate lymphoid cells expressing Thy1, SCA-1, and IL-23R proteins. Genetic disruption of RORgamma in a mouse colitis model dependent on these innate lymphoid cells prevented colitis development ( Buonocore et al., Nature 464: 1371-1375, 2010 ).
  • RORgammaT was shown to play a crucial role in other non-Th17 cells, such as mast cells ( Hueber et al., J. Immunol. 184: 3336-3340, 2010 ).
  • RORgammaT Based on the role of IL-17 producing cells (either Th17 or non-Th17 cells) RORgammaT has been identified as a key mediator in the pathogenesis of several diseases ( Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009 ; Annuziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009 ). This was confirmed using several disease models representative of autoimmune diseases.
  • RORgammaT being a critical mediator in Th17-cells and non-Th17 cells
  • antagonism of the transcriptional activity of RORgammaT is expected to have a beneficial effect on autoimmune diseases, such as but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, and asthma ( Annunziato et al., Nat. Rev. Immunol. 5: 325-331, 2009 ; Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009 ).
  • Antagonism of RORgammaT may also be beneficial in other diseases that are characterized by increased levels of Th17 cells and/or elevated levels of Th17 hallmark cytokines such as IL-17, IL-22 and IL-23.
  • diseases are Kawasaki Disease ( Jia et al., Clin. Exp. Immunol. 162: 131-137, 2010 ) and Hashimoto's thyroiditis ( Figueroa-Vega et al., J. Clin. Endocrinol. Metab. 95: 953-62, 2010 ).
  • Another example includes infectious diseases, such as but not limited to mucosal leishmaniasis ( Boaventura et al., Eur. J. Immunol. 40: 2830-2836, 2010 ). In each of the above examples the inhibition may be enhanced by simultaneous inhibition of RORalpha.
  • agonists include T0901317 and SR1078 ( Wang et al., ACS Chem. Biol. 5:1029-1034, 2010 ).
  • antagonists have been reported such as 7-oxygenated sterols ( Wang et al., J. Biol. Chem. 285: 5013-5025, 2009 ) and compounds described in EP2181710 A1 .
  • psoriasis One exemplary immue disorder in need of better therapy is psoriasis.
  • Various therapeutics have been developed in an attempt to treat psoriasis.
  • the traditional therapies for psoriasis often have toxic adverse effects.
  • An exemplary inflammatory disorder in need of better treatment is rheumatoid arthritis. Numerous therapeutics have been developed in an attempt to treat this disorder. However, some patients develop resistance to current therapies.
  • the present invention provides compounds that alter the interaction of coregulator proteins with RORgammaT, and thereby antagonize RORgammaT-mediated transcriptional activity, such compounds for use for the treatment of RORgammaT-mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases, as well as pharmaceutical compositions comprising such compounds and pharmaceutical carriers.
  • the present invention provides a compound according to Formula Ix or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • the compound having Formula Ix is a compound having Formula Ia and a pharmaceutically acceptable salt or solvate thereof.
  • a third embodiment of the compound having Formula Ix is a compound having Formula Ib and a pharmaceutically acceptable salt or solvate thereof.
  • a first subset of the third embodiment is a compound wherein Y is N.
  • the compound having Formula Id is a compound having Formula Ie and a pharmaceutically acceptable salt or solvate thereof.
  • the compound having Formula Ie is a compound having Formula If and a pharmaceutically acceptable salt or solvate thereof.
  • the compound having Formula If is a compound having Formula Ig and a pharmaceutically acceptable salt or solvate thereof.
  • a 4 , A 5 , A 6 , A 7 are selected from the group consisting of: (i) CR 4 , CR 5 , CR 6 , CR 7 ; (ii) N, CR 5 , CR 6 , CR 7 ; (iii) CR 4 , N, CR 6 , CR 7 ; (iv) CR 4 , CR 5 , N, CR 7 ; (v) CR 4 , CR 5 , CR 6 , N; (vi) N, N, CR 6 ,CR 7 ; (vii) CR 4 , N, N, CR 7 ; (viii) CR 4 , CR 5 , N, N; (ix) N, CR 5 , N, CR 7 ; (x) CR 4 , N, CR 6 , N; and (xi) N, CR 5 , CR 6 , N.
  • a fourth subset of the first embodiment is a compound wherein A 4 , A 5 , A 6 , A 7 is (i) CR 4 , CR 5 , CR 6 , CR 7 ; or (ii) N, CR 5 , CR 6 , CR 7 ; and Y is N.
  • R 1 is (i) (C 3-7 )cycloalkyl or (C 3-5 )heterocycloalkyl, both optionally substituted with one or more R 8 , wherein R 8 is selected from halogen, amino, cyano, nitro, hydroxy, H 2 NC(O)-, (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (di)(C 1-6 )alkylaminocarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one or more halogens; (ii) (C 2-9 )heteroaryl, optionally substituted with one or more R 8 , wherein R 8 is selected from halogen, amino, cyano,
  • R 1 is (C 2-9 )heteroaryl, or (ii) (C 6-14 )aryl, optionally substituted with one, two, three, four or five R 8 .
  • R 8 is selected from halogen, amino, cyano, nitro, hydroxy, (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl, (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one or more halogens.
  • R 1 is (C 6-14 )aryl, optionally substituted with one, two, three, four or five R 8 .
  • R 8 is selected from halogen, cyano, (C 1-3 )-alkoxycarbonyl, (C 1-4 )alkyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one, two or three halogens.
  • R 1 is phenyl, naphthyl, pyridinyl, quinolinyl, benzooxadiazolyl, thiophenyl, isoxazolyl, or benzothiophenyl, each optionally substituted with one or more R 8 .
  • R 8 is selected from halogen, amino, cyano, nitro, hydroxy, (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one or more halogens.
  • R 1 is phenyl, optionally substituted with one, two or three R 8 .
  • R 8 is selected from halogen, amino, cyano, nitro, hydroxy, (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl or (C 1-3 )alkoxy, wherein (C 1-3 )alkoxycarbonyl, (C 1-4 )alkyl and (C 1-3 )alkoxy are optionally substituted with one or more halogens.
  • R 2 is C(O)OH.
  • a still further embodiment of the compounds of Formula Ix, Ia, Ib, Ic, Id, Ie, If or Ig are compounds wherein one of R 4 , R 5 , R 6 , and R 7 is other than hydrogen.
  • the invention also relates to those compounds wherein all specific definitions for A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 ,R 8 , R a , R b , Y, m, n and x and all substituent groups in the various aspects of the inventions defined hereinabove occur in any combination within the definition of the compound of Formula Ix.
  • Non-limiting examples of the compound of the present invention include:
  • the present invention also provides a compound selected from:
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms.
  • an alkyl group contains, for example, from 1 to 6 carbon atoms (C 1 -C 6 alkyl) or from 1 to 3 carbon atoms (C 1 -C 3 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear. In another embodiment, an alkyl group is branched.
  • alkyl includes both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms; for example, “C 1-6 alkyl” (or “C 1 -C 6 alkyl”) includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • Alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments; for example, the term “A-C 4 alkylene-B” represents, for example, A-CH 2 -CH 2 -CH 2 -CH 2 -B, A-CH 2 -CH 2 -CH(CH 3 )-CH 2 -B, A-CH 2 -CH(CH 2 CH 3 )-B, A-CH 2 -C(CH 3 )(CH 3 )-B, and the like.
  • Alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; for example “C 1 -C 6 alkoxy” includes -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -O(CH 2 ) 5 CH 3 , and the like.
  • alkyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, C 1 -C 20 alkyl, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , oxo, CN, N 3 , -OH, -O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, (C 3-7 )cycloalkyl, (C 3-5 )heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(O) 0-2 -, (C 0 -C 6 alkyl)S(O) 0-2 (C 0 -C 6 alkyl)-, (C 0 -C 6 alkyl)
  • alkenyl means a straight or branched carbon chain having the specified number of carbon atoms with at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, 2,4-hexadienyl, and the like.
  • alkynyl means a straight or branched carbon chain having the specified number of carbon atoms with at least one carbon-carbon triple bond.
  • alkynyl include, but are not limited to ethynyl, propargyl, 1-propynyl, 2-butynyl, and the like.
  • carbocycle (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C 3 to C 8 monocyclic, saturated or unsaturated ring or (ii) a C 7 to C 12 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either attached via a bond to, or fused (including spirofused) to, the other ring, and each ring is saturated or unsaturated.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom that results in a stable compound.
  • Saturated carbocyclics form a subset of carbocycles in which the entire ring system (mono- or polycyclic) is saturated.
  • Saturated monocyclic carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • the fused bicyclic carbocycles are a further subset of the carbocycles in which a C 7 to C 10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms (or in the case of spirofused, one carbon atom) are shared by each of the rings in the ring system.
  • a saturated bicyclic carbocycle is one in which both rings are saturated.
  • An unsaturated bicyclic carbocycle is one in which one ring is unsaturated and the other is unsaturated or saturated. Unless otherwise noted, carbocycle is unsubstituted or substituted with C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, halogen, NH 2 or OH.
  • a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
  • Aromatic carbocycles form another subset of the carbocycles.
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems in which the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenyl.
  • cycloalkyl means a cyclic ring of an alkane having the specified total ring carbon atoms; for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • heterocycle broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 7- to 12-membered bicyclic ring system, wherein each ring in (ii) is either attached via a bond to, or fused (including spirofused) to, the other ring, and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally
  • the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • saturated heterocyclics form a subset of the heterocycles; i.e., the term “saturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
  • saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system that consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, 1,4-dioxanyl, 1,4-thioxanyl, tetrahydropyranyl, tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, and tetrahydrothiopyranyl.
  • Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • the term “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic aromatic ring, and that consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • substituted heteroaryl rings containing at least one nitrogen atom e.g., pyridine
  • substitutions can be those resulting in N-oxide formation.
  • monocyclic heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heteroaromatic rings examples include benzotriazolyl, indolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, isoindolyl, indazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrazolo[3,4-b]pyridine, imidazo[2,1-b](1,3)thiazole, (i.e., ), 6-(1-pyrrolyl)-3-pyridyl, 4-(1-pyrrolyl)phenyl, 4-(pyrid-3-yl)phenyl, 4-(pyrid-4-yl)phenyl, and benzothiophenyl (i.e. ).
  • heterocycles are unsaturated heterocycles in which one or both rings are unsaturated (provided the entire ring system is not aromatic).
  • unsaturated heterocycles include dihydrofuranyl, dihydrothienyl, dihydropyranyl, dihydroimidazolyl, indolinyl, isoindolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, 2,3-dihydrobenzofuranyl, 1,4-benzoxazinyl, 1,3-benzoxazolinyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e., ), and benzo-1,3-dioxolyl (i.e., ).
  • phenyl having as a substituent
  • cycloalkyl Unless otherwise specifically noted as only unsubstituted or only substituted, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl (including phenyl) and heteroaryl groups are unsubstituted or substituted (also referred to as "optionally substituted").
  • substituents for substituted or optionally substituted cycloalkyl, cycloalkenyl, aryl (including phenyl, and as an isolated substituent or as part of a substituent such as in aryloxy and aralkyl), heteroaryl (as an isolated substituent or as part of a substituent such as in heteroaryloxy and heteroaralkyl) are one to three groups independently selected from halogen (or halo), C 1 -C 6 alkyl optionally substituted with one to five fluorine, NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , oxo, CN, N 3 , -OH, -O(C 1 -C 6 alkyl) optionally substituted with one to five fluorine, C 3 -C 10 cycloalkyl, (C 3-7 )cycloalkyl, (C 3-5 )heterocycloalkyl, C 2 -C
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).
  • haloalkyl means alkyl having the specified number of carbon atoms in which from one to all of the hydrogen atoms have been replaced by a halogen atom.
  • aralkyl and “heteroaralkyl” refer to an aryl/heteroaryl linked to the rest of the molecule via a C 1 to C 4 alkylene.
  • C 0 as employed in expressions such as "C 0-6 alkylene” means a direct covalent bond; or when employed in expressions such as “C 0-6 alkyl” means hydrogen.
  • an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond; for example, in the structure wherein s is an integer equal to zero, 1 or 2, the structure is when s is zero; or it means that the indicated atom is absent; for example -S(O) 0 - means -S-.
  • an “unsaturated” ring is a partially or fully unsaturated ring.
  • an “unsaturated monocyclic C 6 carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
  • heterocycle described as containing from “ 1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
  • variable definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • variable definitions containing terms having repeated terms e.g., (CRiRj) r , where r is the integer 2, Ri is a defined variable, and Rj is a defined variable
  • the value of Ri may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs.
  • Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CRiRj) 2 can be
  • (C 1-6 )alkyl as used hereinabove means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. Preferred is (C 1-4 )alkyl.
  • (C 1-5 )alkyl means a branched or unbranched alkyl group having 1-5 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and n-pentyl.
  • (C 1-4 )alkyl as used herein means a branched or unbranched alkyl group having 1-4 carbon atoms, being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • (C 1-3 )alkoxy means an alkoxy group having 1-3 carbon atoms, the alkyl moiety being branched or unbranched.
  • (C 1-3 )alkoxycarbonyl means an alkoxycarbonyl group having 1-3 carbon atoms in the alkoxy moiety, the alkoxy moiety having the same meaning as previously defined.
  • (di)(C 1-6 )alkylaminocarbonyl means an alkylaminocarbonyl group, the amino group of which is monosubstituted or disubstituted independently with an alkyl group which contains 1-6 carbon atoms and which has the same meaning as previously defined.
  • Preferred alkyl group is (C 1-4 )alkyl.
  • (C 1-3 )alkoxyaminocarbonyl means an alkoxyaminocarbonyl group, the amino group of which is substituted with an alkoxy group which contains 1-3 carbon atoms and which has the same meaning as previously defined.
  • amino(C 1-4 )alkyloxycarbonyl means an aminoalkyloxycarbonyl group in which the alkyl group contains 1-4 carbon atoms.
  • (C 3-7 )cycloalkyl means a cycloalkyl group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 5-6 Carbon atoms are preferred.
  • (C 3-5 )heterocycloalkyl means a heterocycloalkyl group having 3-5 carbon atoms, including 1-3 heteroatoms selected from N, O and/or S, which may be attached via a nitrogen if feasible, or a carbon atom.
  • Preferred number of heteroatoms is one or two. Most preferred number is one.
  • Preferred heteroatoms are N or O. Most preferred are piperazinyl, tetrahydropyranyl, morpholinyl and pyrrolidinyl.
  • a group having the formula means a heterocyclocarbonyl group such as each optionally substituted with one or more (C 1-10 )alkyl, halogen, amino, cyano, hydroxy, and (C 1-3 )alkoxy.
  • (C 2-9 )heteroaryl means an aromatic group having 2-9 carbon atoms and 1-3 heteroatoms selected from N, O and S, like imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, thiophenyl or furyl, pyrazolyl, isoxazolyl or quinolyl. Preferred number of heteroatoms is one or two. Preferred heteroaryl groups are pyrazolyl, thiophenyl, isoxazolyl, pyridyl and quinolyl.
  • the (C 2-5 )heteroaryl group may be attached via a carbon atom or a nitrogen, if feasible.
  • (C 6-14 )aryl means an aromatic hydrocarbon group having 6-14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, anthracyl, More preferred are (C 6-10 )aryl groups.
  • the most preferred aromatic hydrocarbon group is phenyl.
  • X a -X b shall have the same meaning as the term "X a-b ", wherein X is any atom and a and b are any integers.
  • C 1 -C 4 shall have the same meaning as “C 1-4 ".
  • a x shall have the same meaning, and be interchangeable with, “AX”, wherein “A” is any atom and “x” or “X” are any integer.
  • R 1 shall have the same meaning, and be interchangeable with, "R1".
  • the attachment point is at the last group.
  • (C 1-3 )alkoxycarbonyl refers to, e.g.
  • (C1-4)alkylcarbonyloxy refers to, e.g.
  • substituted means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Stable compound or “stable structure” is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substituent and/or variable when referring to a substituent and/or variable means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound.
  • effective amount refers to an amount of the compound of Formula (Ix) and/or an additional therapeutic agent, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from an RORgammaT-mediated disease or disorder.
  • effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • a “subject” is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a chimpanzee.
  • the compounds of this invention include the hydrates or solvates of the compounds.
  • the compounds of Formula Ix may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (Ix) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (Ix) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
  • the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
  • the above Formula Ix is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula Ix and pharmaceutically acceptable salts thereof.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general Formula Ixmay be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (Ix) may be atropisomers (e.g. substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts and solvates), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources.
  • organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids.
  • Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • the compounds of Formula Ix can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula Ix herein is understood to include reference to salts thereof, unless otherwise indicated.
  • pharmaceutically acceptable salt represents those salts that are, within the scope of medical judgment, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the free base function may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like.
  • the acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium carbonate, ammonium (e.g. diethylamine) or lithium hydroxide.
  • solvates of compounds of Formula Ix.
  • the term "solvate” refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula Ix) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute.
  • solvents include but are not limited to water, ethanol, and acetic acid.
  • the solvent is water, the solvate is known as hydrate; hydrate includes, but is not limited to, hemi-, mono, sesqui-, di- and trihydrates.
  • the compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” may also mean a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the present disclosure includes within its scope the use prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various conditions described with a compound of formula Ix or with a compound that may not be a compound of formula Ix, but that converts to a compound of formula Ix in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985 .
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula Ix or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a discussion of prodrugs and the use of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, 1987 ; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 .
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula Ix.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • isotopically-enriched compounds within generic Formula Ix can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Compounds of the present invention alter the interaction of coregulator proteins with Retinoic Acid Receptor-related Orphan Receptor gamma t (RORgammaT) and thereby antagonize RORgammaT-mediated transcriptional activity, and as such are useful in the treatment of diseases and conditions in which inhibition of RORgammaT is desirable, such as autoimmune and inflammatory diseases and disorders.
  • RORgammaT Retinoic Acid Receptor-related Orphan Receptor gamma t
  • the compounds according to the invention can be used in therapy.
  • a further aspect of the invention resides in a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of RORgammaT-mediated diseases or RORgammaT mediated conditions.
  • Another aspect of the invention resides in a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of autoimmune diseases, in particular those diseases in which Thl7 cells and non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role.
  • autoimmune diseases in particular those diseases in which Thl7 cells and non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role.
  • autoimmune diseases include, but are not limited to, the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis and multiple sclerosis.
  • compounds or a pharmaceutically acceptable salt thereof of the invention can be used for treatment of inflammatory diseases in which Thl7 cells and/or non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to respiratory diseases, osteoarthritis and asthma.
  • compounds or a pharmaceutically acceptable salt thereof of the invention can be used for treatment of infectious diseases in which Th17 cells and/or non-Th17 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to mucosal leishmaniasis.
  • Compounds or a pharmaceutically acceptable salt thereof of the invention can also be used for treatment of other diseases in which Th17 cells and/or non-Thl7 cells, which express Th17 hallmark cytokines, play a prominent role, such as but not limited to Kawasaki disease and Hashimoto's thyroiditis.
  • the disease or condition is an autoimmune disease or inflammatory disease.
  • the disease or condition includes, but is not limited to, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis or mucosal leishmaniasis.
  • the compounds according to the invention can be used in therapies to treat or prevent multiple sclerosis, inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis and mucosal leishmaniasis.
  • the compounds according to the invention can be used to treat or prevent psoriasis.
  • the compounds according to the invention can be used to treat inflammatory bowel disease.
  • the compounds of this invention can be administered for the treatment or prevention of afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal.
  • administration can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral.
  • parenteral refers to modes of administration that include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • the compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • a daily dosage of active ingredient compound will be from about 1.0-2000 milligrams per day. Ordinarily, from 10 to 500 milligrams per day in one or more applications is effective to obtain desired results.
  • These dosages are the effective amounts for the treatment and prevention of afflictions, diseases and illnesses described above, e.g., autoimmune and inflammatory diseases and disorders.
  • compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administration, and the like, all in unit dosage forms for administration.
  • the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
  • the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
  • the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • solid dosage units For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive that does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • compositions comprising a compound or a pharmaceutically acceptable salt or solvate thereof of the invention and one or more pharmaceutically acceptable excipients.
  • excipient and “carrier” may be used interchangeably.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound represented by Formula Ix (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.
  • the active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions.
  • dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol , a standard reference text in this field.
  • the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of the invention in suitable propellants, such as fluorocarbons or hydrocarbons.
  • MDI metered dose inhalation
  • an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of the invention in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
  • Useful pharmaceutical dosage-forms for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
  • the capsules are washed and dried.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
  • An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • the same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent.
  • the dosage form and administration route should be selected depending on the compatibility of the combined drugs.
  • coadministration is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents.
  • the auxiliaries must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • the exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.
  • a dosage for humans preferably contains 0.0001-100 mg per kg body weight.
  • the desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day.
  • the dosage as well as the regimen of administration may differ between a female and a male recipient.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and the use of at least one other pharmaceutically active agent.
  • the compound(s) of the invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of the invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a compound of the invention may be combined with one or more other active agents such as: (1) TNF-a inhibitors; (2) non-selective COX-I/COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for treatment of inflammatory and autoimmune diseases including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclo
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical composition.
  • Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • compositions of the present invention include those that also comprise at least one additional therapeutically active agent, in addition to the compound of the invention.
  • the invention further includes a compound of the present invention in combination with one or more other drug(s).
  • Scheme 1 illustrates a general method toward the preparation of compounds of formula I.
  • N-acylation with either carboxylic acids or acid chloride in the presence of base led to the formation of compound B.
  • Subsequent Suzuki coupling followed by ester hydrolysis afforded the final compound.
  • ester hydrolysis occurred under the Suzuki coupling condition and led to the formation of final product within one pot.
  • Scheme 2 illustrates a general method for the preparation of compounds of formula I that contain an amide moiety at A 6 position.
  • acylation followed by ester hydrolysis gave intermediate B.
  • Standard amide coupling furnished intermediate C.
  • Subsequent Suzuki coupling followed by ester hydrolysis led to the formation of the final product I.
  • Scheme 3 illustrates an alternative method for the preparation of compounds of formula I that contain an amide moiety at A 6 position.
  • N-acylation followed by Suzuki coupling gave intermediate C.
  • Selective ester hydrolysis and subsequent amide coupling led to the formation of compound D.
  • Final t-Bu removal under acidic conditions gave the desired product I.
  • Scheme 4 illustrates a general method toward the preparation of compounds of formula I that contain a cyclohexyl instead of cyclohexenyl motif.
  • halide A which can be obtained following those methods described previously, hydrogenation led to the formation of saturated cyclohexyl intermediate B. Ester hydrolysis gave the desired product I.
  • Scheme 5 illustrates a general method for the preparation of compounds of formula I that often are more difficult to access in comparison to those from general methods described previously.
  • N-acylation followed by carbonylation gave intermediate C.
  • Ester hydrolysis, Weinreb formation, and vinyl Grignard addition led to the formation of key intermediate E.
  • Condensation with ⁇ -ketone ester afforded two region-isomers F and G.
  • Final ester hydrolysis gave the final product I.
  • Corresponding saturated cyclohexyl analogs could also be obtained from either intermediate F or G via hydrogenation and ester hydrolysis.
  • Example i-1 Preparation of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (i-1).
  • Step 1 Preparation of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (i-1b).
  • Step 4 Preparation of ethyl 1-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (i-1e).
  • Step 1 Preparation of 3-bromo-4-fluoro-1H-indazole (i-3b).
  • a solution of 4-fluoro-1H-indazole (i-3a) in 2M sodium hydroxide solution (100 ml) at room temperature was added a solution of bromine(5.8 g, 36.8 mmol) in 2M sodium hydroxide solution (60 ml).
  • the reaction mixture was stirred at room temperature for 3h.
  • sodium bisulfite aqueous solution (10%, 100mL).
  • the solution was extracted with ethyl acetate (2x150mL).
  • Step 2 Preparation of (3-bromo-4-fluoro-1H-indazol-1-yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone (i-3).
  • 3-bromo-4-fluoro-1H-indazole (i-3b) 3.2 g, 14.9mmol
  • 2-chloro-6-(trifluoromethyl)benzoyl chloride 5.43g, 22.35mmol
  • DMAP (1.82 g, 14.9 mmol
  • TEA 3.02g, 29.8 mmol
  • Example i-4 (4-chloro-3-iodo-1H-indazol-1-yl)(2-chloro-6-(trifluoromethyl)phenyl) methanone
  • Methyl 2-bromo-6-chlorobenzoate (i-5a) (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc) 2 (90 mg, 0.4 mmol), Cy 3 P (224 mg, 0.8 mmol) and K 3 PO 4 (2.5 g, 12.0 mmol) were mixed in toluene (20 ml) and H 2 O (2.5 ml). The mixture was stirred at 100°C overnight under N 2 atmosphere. The mixture was cooled down and poured into water (50 ml). The mixture was extracted with EA (50 ml). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.
  • Step 1 Preparation of 1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazole-6-carboxylate (i-7b).
  • methyl 3-iodo-1H-indazole-6-carboxylate (i-7a) 1.5 g, 4.97 mmol
  • TEA 1.730 ml, 12.41 mmol
  • DMAP 0.061 g, 0.497 mmol
  • DCM 9.93 ml
  • 2-chloro-6-cyclopropylbenzoyl chloride 1.282 g, 5.96 mmol
  • the resulting solution was allowed to stir at room temperature for 3 hours.
  • the mixture was diluted with ethyl acetate, washed 2x with aqueous sodium hydrogen carbonate and 1x with brine.
  • Step 2 Preparation of 1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazole-6-carboxylic acid (i-7).
  • Example i-8 Preparation of 3-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-yl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazole-6-carboxylic acid
  • Step 1 methyl 3-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-yl)-1-(2-chloro-6-(trifluoro methyl)benzoyl)-1H-indazole-6-carboxylate (i-8b).
  • Step 2 Preparation of 3-(4-(tert-butoxycarbonyl)cyclohex-1-en-1-yl)-1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazole-6-carboxylic acid (i-8).
  • Example i-9 1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-N-methoxy-N-methyl-1H-indazole-3-carboxamide.
  • Step 1 Preparation of ethyl 1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazole-3-carboxylate (i-9b).
  • Example i-10 (2-chloro-6-(trifluoromethyl)phenyl)(3-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)methanone
  • Step 1 ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (i-11b).
  • Step 2 Preparation of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (i-11c).
  • Step 3 Preparation of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane carboxylate (i-12d).
  • Step 4 Preparation of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclo hexanecarboxylate (i-12e).
  • Example 1 A Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethyl carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (1A)
  • Step 1 Preparation of methyl 1H-indazole-6-carboxylate (A-2).
  • Methyl 1H-indazole-6-carboxylate (A-2) (5.0 g, 28.3 mmol) was dissolved in anhydrous DMAC (50 mL). Iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 113.5 mmol) were added in portions while stirring at 0 °C. The ice bath was removed and the mixture was stirred at room temperature for 1h. The reaction was monitored by TLC (25% MeOH in chloroform) then it was slowly quenched with Na 2 S 2 O 3 (sat. sol. in water, 100 mL), diluted with water (50 mL) and extracted with EtOAc (3x100 mL).
  • Step 3 Preparation of methyl 1-(2-chloro-6-(trifluoromethyl)benzoyl)-3-iodo-1H-indazole-6-carboxylate (A-4).
  • Step 4 Preparation of 1-(2-chloro-6-(trifluoromethyl)benzoyl)-3-iodo-1H-indazole-6-carboxylic acid (A-5).
  • Step 5 Preparation of 1-(2-chloro-6-(trifluoromethyl)benzoyl)-3-iodo-N,N-dimethyl-1H-indazole-6-carboxamide (A-6).
  • Step 6 Preparation of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylate (A-7).
  • Step 7 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethyl carbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (1A).
  • a mixture of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(dimethylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylate (A-7) (37 mg, 0.07 mmol) and LiOHH 2 O (16mg, 0.37mmmol) in 10 ml THF/10 ml H 2 O was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in water. HCl (5% sol in water) was added until pH 4-5 was acheived.
  • Step 1 Preparation of 4-fluoro-3-iodo-1H-indazole (B-2).
  • B-1 4-fluoroindazole (B-1) (5.00 g, 36.73 mmol) in DMF (80 mL)
  • I 2 18.64 g, 73.46 mmol
  • KOH 7.73 g, 137.7 mmol
  • TLC TLC indicated that the reaction was complete.
  • the reaction mixture was poured into aq. NaHSO 3 (10%, 200 mL) and extracted with EA (3x200 mL).
  • Step 2 Preparation of (2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3-iodo-1H-indazol-1-yl)methanone (B-3).
  • compound B-2 5.24 g, 20 mmol
  • 2-chloro-6-(trifluoromethyl)benzoyl chloride (4.86 g, 20 mmol)
  • DMAP 2.44 g, 20 mmol
  • DCM 30mL
  • the reaction was stirred at room temperature for 3 minutes.
  • TEA 5.8 mL, 40 mmol
  • the reaction mixture was stirred at room temperature overnight. LCMS indicated little starting material remaining.
  • Step 3 Preparation of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylatee (B-4).
  • B-3 300 mg, 0.64 mmol
  • 4-(ethoxycarbonyl)-4-methylcyclohex-1-enylboronic acid 203 mg, 0.96 mmol
  • Pd(dppf)Cl 2 52.2 mg, 0.064 mmol
  • KOAc 190 mg, 1.92mmol
  • Step 4 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (B-5).
  • HCl (2mol/L) was added slowly to maintain the PH ⁇ 7.
  • the mixture was concentrated under reduced pressure, and filtered to afford a white solid.
  • the white solid was washed with H 2 O and dried to yield 100 mg of white solid 1B.
  • Example 2A and 2B Preparation of (R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (2A) and (S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (2B)
  • Step 1 Preparation of (1-(2-chloro-6-cyclopropylbenzoyl)-3-iodo-1H-indazol-6-yl)(3-methoxyazetidin-1-yl)methanone (C-1).
  • Step 2 Preparation of tert-butyl 4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylate (C-2).
  • the reaction was degassed with argon for 5 minutes.
  • potassium phosphate tribasic 700 ⁇ l, 1.400 mmol
  • the resulting solution was heated to 80°C overnight.
  • the mixture was cooled, diluted with ethyl acetate, washed 2x with aqueous sodium hydrogen carbonate and 1x with brine.
  • Aqueous layers were back extracted once with ethyl acetate, combined organic layers were dried over Na2SO 4 , filtered and the solvent was evaporated under reduced pressure.
  • the residue was purified by Prep-HPLC (Acetonitrile/Water + 0.10% TFA 50-100%) to give the desired product as a colorless solid.
  • Step 3 Preparation of (R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (2A)
  • Step 4 Preparation of (S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxy azetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (2B).
  • Preparation was similar to that for the other enantiomeric ester (peak2, C-2b ) , and can be achieved by those of ordinary skill in the art of organic synthesis in light of the present disclosure.
  • Table 2 Chemical Name Structure LCMS [M+H] + Found 2C (R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-1H-indazol-3-yl)-1-methylcyclohex-3-enecarboxylic acid 548 2D (S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-methoxyazetidine-1-carbonyl)-1H-indazol-3-yl)-1-methylcyclohex-3-enecarboxylic acid 548
  • Example 3A and 3B Preparation (R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-lH-indazol-3-yl)cyclohex-3-enecarboxylic acid (3A) and (S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-lH-indazol-3-yl)cyclohex-3-enecarboxylic acid (3B)
  • Step 1 Preparation of tert-butyl 4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylate (D-1).
  • Step 2 Preparation (R or S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (3A) To a vial was added tert-butyl 4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylate (peak1, D-la, 26 mg, 0.053 mmol), DCM (2 mL), and TFA (0.202 mL, 2.63 mmol). The solution was stirred for two days.
  • Step 4 Preparation (S or R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (3B).
  • Preparation was similar to that for the other enantiomeric ester (peak2, D-1b ) , and can be achieved by those of ordinary skill in the art of organic synthesis in light of the present disclosure.
  • Example 4A Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3,3-difluoroazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid
  • Step 1 Preparation of tert-Butyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3,3-difluoroazetidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylate (E-1).
  • Step 2 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-6-(3,3-difluoroazetidin e-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-enecarboxylic acid (4A).
  • Step 1 Preparation of 4-fluoro-1-tosyl-1H-indole (F-1).
  • Step 2 Preparation of 3-bromo-4-fluoro-1-tosyl-1H-indole (F-2).
  • Step 3 Preparation of tert-butyl 4-(4-fluoro-1-tosyl-1H-indol-3-yl)cyclohex-3-ene carboxylate (F-3).
  • Step 4 Preparation of tert-butyl 4-(4-fluoro-1H-indol-3-yl)cyclohex-3-enecarboxylate (F-4).
  • tert-butyl 4-(4-fluoro-1-tosyl-1H-indol-3-yl)cyclohex-3-enecarboxylate (F-3) (550 mg, 1.171 mmol), THF (3904 ⁇ l), ethanol (7809 ⁇ l) and KOH (657 mg, 11.71 mmol) and the reaction was allowed to stir at room temperature for 2 hours.
  • the reaction mixture was diluted with methanol and filtered.
  • the resulting solution was concentrated and the residue was diluted with ethyl acetate, washed 2x with aqueous sodium hydrogen carbonate and 1x with brine.
  • Step 5 Preparation of tert-butyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indol-3-yl)cyclohex-3-enecarboxylate (F-5).
  • Step 6 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indol-3-yl)cyclohex-3-enecarboxylic acid (5A).
  • Example 6A and 6B Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxycyclohex-3-enecarboxylic acid (6A) and 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6-hydroxycyclohex-3-enecarboxylic acid (6B)
  • Step 2 Preparation of ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-oxocyclohex-3-enecarboxylate (G-2a) and ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6-oxocyclohex-3-enecarboxylate (G-2b).
  • Step 5 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6-hydroxycyclohex-3-enecarboxylic acid (6B).
  • Preparation from the other regioisomer G-2b was similar to the preparation of 6A, and can be achieved by those of ordinary skill in the art of organic synthesis in light of the present disclosure.
  • Example 7A, 7B and 7C Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-methylcyclohexanecarboxylic acid (7A) (provided for reference)
  • Step 1 Preparation of (3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylcyclohexyl)-4-fluoro-1H-indazol-1-yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone (H-1).
  • Example 8A and 8B Preparation of ( trans )-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid (8A) and ( cis )-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid (8B). (Example 8B provided for reference)
  • Step 2 Preparation of (trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid (8A) and (cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohexanecarboxylic acid (8B).
  • Example 9A and 9B Preparation of (trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-l-methyleyclohexanecarboxylic acid (9A) and (cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylic acid (9B) (Example 9B provided for reference)
  • Step 1 Preparation of ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylate (J-1).
  • Step 2 Preparation of (trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylic acid (9A) and (cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-1-methylcyclohexanecarboxylic acid (9B).
  • Example 10A and 10B Preparation of (R and S)-4-(1-(2-chloro-6-(trifluoro methyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylic acid (10A) and (R and S) 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylic acid (10B).
  • Step 1 Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1).
  • Step 2 Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2).
  • Step 3 Preparation of mixture of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylate and methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylate (K-3).
  • Step 4 Preparation of (R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylic acid (10A) and (R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylic acid (10B).
  • Example 11A and 11B Preparation of (trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid (11A) and (cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid (11B). (Example 11B provided for reference)
  • Step 1 Preparation of ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohex-3-enecarboxylate (L-1).
  • Step 2 Preparation of ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b] pyridin-3-yl)cyclohexanecarboxylate (L-2).
  • Step 3 Preparation of (trans)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid (11A) and (cis)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohexanecarboxylic acid (11B).
  • Step 1 Preparation of ethyl 3-methyl-4-oxocyclohexanecarboxylate (M-1).
  • Step 2 Preparation of ethyl 5-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (M-2).
  • Step 3 Preparation of ethyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (M-3).
  • Step 4 Preparation of ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-5-methylcyclohex-3-enecarboxylate (M-4).
  • Step 5 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-5-methylcyclohex-3-enecarboxylic acid (12A).
  • Example 13A Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxycyclohexanecarboxylic acid (provided for reference).
  • Step 1 Preparation of (trans or cis) ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxycyclohexanecarboxylate (N-1a) and (cis or trans)-ethyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxycyclohexaneca rboxylate (N-1b).
  • Step 2 Preparation of 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-4-hydroxycyclohexanecarboxylic acid (13A).
  • the compounds of the invention inhibit RORgammaT activity.
  • Activation of RORgammaT activity can be measured using, e.g., biochemical TR-FRET assay.
  • TR-FRET technique is a sensitive biochemical proximity assay that will give information concerning the interaction of a ligand with the LBD, in the presence of cofactor-derived peptides ( Zhou et al., Methods 25:54-61, 2001 ).
  • HIS-tagged ROR ⁇ -LBD protein was expressed in SF9 cells using a baculovirus expression system.
  • the ROR ⁇ -LBD protein was purified by glutathione sepharose chromatography. Separately, SF9 cells not expressing any recombinant protein were lysed and the lysate was added to the purified ROR ⁇ -LBD at 0.25 ⁇ l lysate (from 10,000 SF9 cells)/nM purified protein. The mixture was then diluted in assay buffer (50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT) to obtain ROR ⁇ -LBD final concentration of 3 nM in 384-well assay plate.
  • assay buffer 50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT
  • a stock of biotinylated-LXXLL peptide from coactivator SRC1 (Biotin-CPSSHSSLTERHKILHRLLQEGSPS) (SEQ ID NO:2) was prepared in assay buffer and added to each well (100 nM final concentration).
  • IC50 values for test compounds were calculated from the quotient of the fluorescence signal at 665 nm divided by the fluorescence signal at 615 nm.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)

Claims (26)

  1. Composé selon la formule Ix
    Figure imgb0142
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, dans laquelle :
    X est C(O) ;
    Y est N, CH ou CRa ;
    n = 0, 1, 2, 3 ou 4 ;
    A4 est CR4 ou N,
    A5 est CR5 ou N,
    A6 est CR6 ou N,
    A7 est CR7 ou N,
    avec la condition que pas plus de deux de A4-A7 ne peuvent être N ;
    Ra est alkyle en C1-4 ;
    R1 est
    (i) carbocyclyle en C3-12 ; ou
    (ii) hétérocyclyle de 4 à 12 chaînons,
    chacun de (i) et (ii) sont éventuellement substitués par un, deux, trois, quatre ou cinq R8 ;
    R2 est hydroxycarbonyle, hydroxycarbonyl-alkyle en C1-10, ou carbamoyle ;
    R3 est hydrogène, halogène, cyano, nitro, hydroxyle, alkyle en C1-3-C(O)O-, alkyle en C1-4, ou alcoxyle en C1-4,où alkyle en C1-4 et alcoxyle en C1-4 sont éventuellement substitués par un ou plusieurs halogènes ;
    R4-R7 sont indépendamment H, halogène, amino, cyano, hydroxyle, alcoxyle en C1-3, alkyle en C1-4, (alkyle en C0-10)-aminocarbonyle, (di) (alkyle en C1-6)-aminocarbonyle ou aminoalkyle en C1-4, où alcoxyle en C1-3, alkyle en C1-4, (alkyle en C0-10)-aminocarbonyle, (di) (alkyle en C1-6)-aminocarbonyle et aminoalkyle en C1-4 sont éventuellement substitués par un ou plusieurs halogènes, hydroxyle ou alcoxyle en C1-3 ; ou un groupe possédant la formule
    Figure imgb0143
     éventuellement substitué par un ou plusieurs des suivants : alkyle en C1-10, halogène, amino, cyano, hydroxyle, alcoxyle en C1-3, et où m est 1, 2, 3 ou 4 ;
    R8 est halogène, cyano, amino, nitro, hydroxyle, H2NC(O)-, (alcoxyle en C1-3)-carbonyle, (di) (alkyle en C1-6)-aminocarbonyle, alkyle en C1-4, cycloalkyle en C3-7, hétérocycloalkyle en C3-5, (alcoxyle en C1-3)-aminocarbonyle, (hétérocyclyle à 4 à 8 chaînons) -carbonyle, (cycloalkyle en C3-6)-aminocarbonyle, amino (alkyle en C1-4)-oxycarbonyle ou alcoxyle en C1-3, où (alcoxyle en C1-3)-carbonyle, (di) (alkyle en C1-6)-aminocarbonyle, alkyle en C1-4, (alcoxyle en C1-3)-aminocarbonyle, (hétérocyclyle à 4 à 8 chaînons)-carbonyle, cycloalkyle en C3-6)-aminocarbonyle, amino(alkyle en C1-4)-oxycarbonyle et alcoxyle en C1-3 sont éventuellement substitués par oxo, alkyle en C1-4, hydroxyalkyle en C1-3, ou un, deux ou trois halogènes.
  2. Composé de la revendication 1 possédant la formule Ia
    Figure imgb0144
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  3. Composé de la revendication 1 ou 2, dans lequel R8 est halogène, cyano, amino, nitro, hydroxyle, H2NC(O)-, (alcoxyle en C1-3)-carbonyle, (di) (alkyle en C1-6)-aminocarbonyle, alkyle en C1-4, cycloalkyle en C3-7, hétérocycloalkyle en C3-5, alcoxyle en C1-3, où (alcoxyle en C1-3)-carbonyle, (di) (alkyle en C1-6)-aminocarbonyle, alkyle en C1-4 et alcoxyle en C1-3 sont éventuellement substitués par un, deux ou trois halogènes.
  4. Composé de la revendication 1 possédant la formule Ib ou Ic
    Figure imgb0145
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  5. Composé de l'une quelconque des revendications précédentes, dans lequel R1 est phényle, éventuellement substitué par un, deux, trois, quatre, ou cinq R8, où R8 est halogène, amino, cyano, nitro, (alcoxyle en C1-3)-carbonyle, alkyle en C1-4 ou alcoxyle en C1-3, où (alcoxyle en C1-3)-carbonyle, alkyle en C1-4 ou alcoxyle en C1-3 sont éventuellement substitués par un, deux ou trois halogènes.
  6. Composé de la revendication 1 ou 2 possédant la formule Id
    Figure imgb0146
     dans laquelle x est 1, 2, 3, 4, ou 5,
    ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  7. Composé de la revendication 6 possédant la formule Ie
    Figure imgb0147
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  8. Composé de l'une quelconque des revendications 1 à 7, dans lequel Y est N.
  9. Composé de la revendication 7 possédant la formule If
    Figure imgb0148
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  10. Composé de la revendication 9 possédant la formule Ig
    Figure imgb0149
     ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci.
  11. Composé de l'une quelconque des revendications 1 à 4, dans lequel R1 est phényle, éventuellement substitué par un, deux ou trois R8.
  12. Composé de la revendication 11, dans lequel R2 est C(O)OH.
  13. Composé de l'une quelconque des revendications 1 à 12, dans lequel A4, A5, A6, A7 est (i) CR4, CR5, CR6, CR7 ; ou (ii) N, CR5, CR6, CR7.
  14. Composé selon la revendication 1 choisi parmi :
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(diméthylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(2-hydroxyéthylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1-méthylcyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-2-méthylcyclohex-3-ènecarboxylique ; et
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique.
  15. Composé selon la revendication 1 choisi parmi :
    acide 4-(4-chloro-1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-indazol-3-yl)-1-méthylcyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-1-méthylcyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-méthylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-méthylbenzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)cyclohex-3-ènecarboxylique ;
    acide (R ou S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-méthoxyazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide (S ou R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-méthoxyazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide (R ou S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-méthoxyazétidine-1-carbonyl)-1H-indazol-3-yl)-1-méthylcyclohex-3-ènecarboxylique ;
    acide (S ou R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-6-(3-méthoxyazétidine-1-carbonyl)-1H-indazol-3-yl)-1-méthylcyclohex-3-ènecarboxylique ;
    acide (R ou S)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide (S ou R)-4-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(3,3-difluoroazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(cyclopropylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(cyclopropyl(méthyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(6-(azétidine-1-carbonyl)-1-(2-chloro-6-(trifluorométhyl)benzoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(3-méthoxyazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(pyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((S)-2-méthylpyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((R)-2-méthylpyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(3-méthoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(2-méthylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(cyclohexyl(méthyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(morpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((2R,6S)-2,6-diméthylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(4-méthyl-3-oxopipérazine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((S)-3-méthylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(méthyl(tétrahydro-2H-pyran-4-yl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((R)-3-méthylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((S)-2-méthylmorpholine-4-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((2-hydroxyéthyl)(méthyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(isopropylcarbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(isopropyl(méthyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((2-méthoxyéthyl)(méthyl)carbamoyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(3-hydroxyazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(3-fluoroazétidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(pipéridine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-(((1-hydroxy-3-(méthylamino)propan-2-yl)oxy)carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((S)-3-méthoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-6-((R)-3-méthoxypyrrolidine-1-carbonyl)-1H-indazol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indol-3-yl)cyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxycyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6-hydroxycyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxy-6-méthylcyclohex-3-ènecarboxylique ;
    acide (R et S)-4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-diméthylcyclohex-3-ènecarboxylique ;
    acide (R et S)-4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-diméthylcyclohex-3-ènecarboxylique ;
    acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-5-méthylcyclohex-3-ènecarboxylique ;
  16. Composé selon la revendication 1, le composé étant l'acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indol-3-yl)cyclohex-3-ènecarboxylique.
  17. Composé selon la revendication 1, le composé étant l'acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxycyclohex-3-ènecarboxylique.
  18. Composé selon la revendication 1, le composé étant l'acide 4-(1-(2-chloro-6-(trifluorométhyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2-hydroxy-6-méthylcyclohex-3-ènecarboxylique.
  19. Composé choisi parmi :
    Figure imgb0150
  20. Composition pharmaceutique comprenant un composé de l'une quelconque des revendications précédentes ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables, éventuellement dans laquelle la composition pharmaceutique comprend en outre au moins un agent thérapeutiquement actif additionnel.
  21. Composition pharmaceutique comprenant un composé de la revendication 16 ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables.
  22. Composition pharmaceutique comprenant un composé de la revendication 17 ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables.
  23. Composition pharmaceutique comprenant un composé de la revendication 18 ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables.
  24. Composé de l'une quelconque des revendications 1 à 19, ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci, pour utilisation dans le traitement d'une maladie ou d'une pathologie régulée par le récepteur orphelin apparenté au récepteur de l'acide rétinoïque gamma t (RORgammaT).
  25. Composé pour utilisation de la revendication 24, dans laquelle la maladie ou la pathologie est une maladie auto-immune ou une maladie inflammatoire.
  26. Composé pour utilisation de la revendication 24, dans laquelle la maladie ou la pathologie est la sclérose en plaques, la maladie inflammatoire de l'intestin, la maladie de Crohn, spondylarthrite ankylosante, le psoriasis, l'arthrite rhumatoïde, l'asthme, l'ostéoarthrite, la maladie de Kawasaki, la thyroïdite de Hashimoto ou la leishmaniose muqueuse.
EP13829099.4A 2012-08-15 2013-08-14 Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl comme inhibiteurs de ror-gamma-t et leur utilisation Active EP2884976B1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
SI201331578T SI2884976T1 (sl) 2012-08-15 2013-08-14 Indolne in indazolne spojine, substituirane s 3-cikloheksenilom in cikloheksilom, kot zaviralci receptorja RORgamaT in njihova uporaba teh spojin
RSP20191289 RS59364B1 (sr) 2012-08-15 2013-08-14 Jedinjenja indola i indazola supstituisana 3-cikloheksenilom i cikloheksilom kao inhibitori rorgamat i njihove upotrebe
PL13829099T PL2884976T3 (pl) 2012-08-15 2013-08-14 Związki indolowe i indazolowe podstawione ugrupowaniem 3- cykloheksenylowym i cykloheksylowym jako inhibitory receptora ror-gamma-t oraz ich wykorzystanie
MEP-2019-276A ME03579B (fr) 2012-08-15 2013-08-14 Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl
HRP20191654 HRP20191654T1 (hr) 2012-08-15 2019-09-13 3-CIKLOHEKSENIL I CIKLOHEKSIL SUBSTITUIRANI SPOJEVI INDOLA I INDAZOLA KAO INHIBITORI RORgamaT I NJIHOVA UPORABA

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/CN2012/080133 WO2014026328A1 (fr) 2012-08-15 2012-08-15 Composés d'indazole et d'indole à substitution 3-cyclohexényle en tant qu'inhibiteurs de rorgammat et leurs utilisations
PCT/US2013/054902 WO2014028597A2 (fr) 2012-08-15 2013-08-14 Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl

Publications (3)

Publication Number Publication Date
EP2884976A2 EP2884976A2 (fr) 2015-06-24
EP2884976A4 EP2884976A4 (fr) 2016-04-06
EP2884976B1 true EP2884976B1 (fr) 2019-07-24

Family

ID=50101186

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13829099.4A Active EP2884976B1 (fr) 2012-08-15 2013-08-14 Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl comme inhibiteurs de ror-gamma-t et leur utilisation

Country Status (21)

Country Link
US (1) US9487490B2 (fr)
EP (1) EP2884976B1 (fr)
JP (1) JP6232429B2 (fr)
KR (1) KR20150041800A (fr)
CN (1) CN104822376A (fr)
AU (1) AU2013302644A1 (fr)
BR (1) BR112015003332A2 (fr)
CA (1) CA2881696A1 (fr)
CY (1) CY1122272T1 (fr)
DK (1) DK2884976T3 (fr)
ES (1) ES2749713T3 (fr)
HR (1) HRP20191654T1 (fr)
HU (1) HUE045379T2 (fr)
LT (1) LT2884976T (fr)
ME (1) ME03579B (fr)
PL (1) PL2884976T3 (fr)
PT (1) PT2884976T (fr)
RS (1) RS59364B1 (fr)
RU (1) RU2015108898A (fr)
SI (1) SI2884976T1 (fr)
WO (2) WO2014026328A1 (fr)

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2487159A1 (fr) 2011-02-11 2012-08-15 MSD Oss B.V. Inhibiteurs du RORgammaT
WO2014026330A1 (fr) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés 3-aminocycloalkyles en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2014026329A1 (fr) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'indazole et d'indole n-alkylés en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2014026327A1 (fr) 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2015015378A2 (fr) * 2013-08-02 2015-02-05 Pfizer Inc. Inhibiteurs de rorc2 méthodes d'utilisation associées
EA031804B1 (ru) 2014-02-03 2019-02-28 Вайтаи Фармасьютиклз, Инк. Дигидропирролопиридиновые ингибиторы ror-гамма
MX2016010998A (es) 2014-02-27 2017-03-31 Lycera Corp Terapia celular adoptiva que usa un agonista de receptor huérfano gamma relacionado con receptor de ácido retinoico y métodos terapéuticos relacionados.
CA2947290A1 (fr) 2014-05-05 2015-11-12 Lycera Corporation Sulfonamide de tetrahydroquinoline et composes apparentes destines a servir d'agonistes de rory et pour le traitement de maladies
EP3209641A4 (fr) 2014-05-05 2018-06-06 Lycera Corporation Benzènesulfonamido et composés apparentés utilisés en tant qu'agonistes de ror et pour le traitement de maladie
WO2016014918A1 (fr) * 2014-07-25 2016-01-28 Innov 17 Llc Modulateurs à base de benzimidazole du récepteur orphelin lié au récepteur de l'acide rétinoïque et leurs utilisations
EP3172196A4 (fr) * 2014-07-25 2017-12-27 Innov17 LLC Modulateurs du récepteur orphelin lié au récepteur de l'acide azaindole rétinoïque et leurs utilisations
US20160024057A1 (en) * 2014-07-25 2016-01-28 Innov17 Llc Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof
WO2016014910A1 (fr) * 2014-07-25 2016-01-28 Innov17 Llc Modulateurs à base de sulfamide du récepteur orphelin lié au récepteur de l'acide rétinoïque et leurs utilisations
MA40759A (fr) * 2014-09-26 2017-08-01 Pfizer Modulateurs de rorc2 de type pyrrolopyridine substitué par un méthyle et trifluorométhyle et leurs procédés d'utilisation
JP6564029B2 (ja) 2014-10-14 2019-08-21 ヴァイティー ファーマシューティカルズ，エルエルシー Ｒｏｒ−ガンマのジヒドロピロロピリジン阻害剤
GB201419015D0 (en) 2014-10-24 2014-12-10 Orca Pharmaceuticals Ltd Compounds
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
BR112017014770A2 (pt) * 2015-01-08 2018-01-16 Advinus Therapeutics Ltd compostos bicíclicos, composições e aplicações médicas dos mesmos
EP3252038B1 (fr) * 2015-01-28 2020-04-08 Beijing Hanmi Pharmaceutical Co., Ltd. Dérivé de benzopyrroline-2-one substitué par groupe n-benzoate et son utilisation
US10385036B2 (en) 2015-01-30 2019-08-20 Pfizer Inc. Sulfonamide-substituted indole modulators of RORC2 and methods of use thereof
EP3256450B1 (fr) 2015-02-11 2020-12-02 Merck Sharp & Dohme Corp. Composés pyrazole substitués utilisés en tant qu'inhibiteurs de ror-gamma-t et utilisations desdits composés
WO2016128908A1 (fr) * 2015-02-12 2016-08-18 Advinus Therapeutics Limited Composés bicycliques, compositions et applications médicinales correspondantes
JP2018513123A (ja) 2015-03-12 2018-05-24 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Ｒｏｒガンマ阻害剤を用いてがんを治療するための方法
JP2018515491A (ja) 2015-05-05 2018-06-14 リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ ＲＯＲγの作動薬及び疾患の療法として使用するジヒドロ−２Ｈ−ベンゾ［ｂ］［１，４］オキサジンスルホンアミド及び関連化合物
LT3307734T (lt) * 2015-06-09 2020-05-11 Abbvie Inc. Branduolinio receptoriaus moduliatoriai (ror), skirti uždegiminių ir autoimuninių ligų gydymui
WO2016198908A1 (fr) * 2015-06-09 2016-12-15 Abbvie Inc. Modulateurs des récepteurs nucléaires ror
KR20180025894A (ko) 2015-06-11 2018-03-09 라이세라 코퍼레이션 Rory의 작용제로서 사용하기 위한 아릴 디히드로-2h-벤조[b][1,4]옥사진 술폰아미드 및 관련 화합물 및 질환의 치료
ES2856931T3 (es) 2015-08-05 2021-09-28 Vitae Pharmaceuticals Llc Moduladores de ROR-gamma
AR105821A1 (es) * 2015-09-09 2017-11-15 Lilly Co Eli COMPUESTOS ÚTILES PARA INHIBIR ROR-g-T
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
EP3368516B1 (fr) * 2015-10-27 2020-07-15 Merck Sharp & Dohme Corp. Composés pyrazoles bicycliques substitués en tant qu'inhibiteurs de rorgammat et leurs utilisations
KR20180070697A (ko) * 2015-10-27 2018-06-26 머크 샤프 앤드 돔 코포레이션 Ror감마t 저해제로서의 치환된 인다졸 화합물 및 이의 용도
EP3377482B1 (fr) 2015-11-20 2021-05-12 Vitae Pharmaceuticals, LLC Modulateurs de ror-gamma
TW202220968A (zh) 2016-01-29 2022-06-01 美商維它藥物有限責任公司 ＲＯＲ－γ調節劑
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
CN110337437B (zh) 2016-12-28 2023-02-03 达特神经科学有限公司 作为pde2抑制剂的取代的吡唑并嘧啶酮化合物
JP2020111510A (ja) * 2017-03-29 2020-07-27 科研製薬株式会社 インダゾール誘導体及びそれを含有する医薬
EP3609883B1 (fr) * 2017-04-11 2022-06-29 Sunshine Lake Pharma Co., Ltd. Composés indazole substitués par fluor et leurs utilisations
TW201906816A (zh) * 2017-07-06 2019-02-16 大陸商江蘇恆瑞醫藥股份有限公司 吲哚甲醯胺類衍生物、其製備方法及其在醫藥上的應用
AR112461A1 (es) 2017-07-24 2019-10-30 Vitae Pharmaceuticals Inc PROCESOS PARA LA PRODUCCIÓN DE SALES Y FORMAS CRISTALINAS DE INHIBIDORES DE RORg
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
KR20200108419A (ko) 2017-11-27 2020-09-18 다트 뉴로사이언스, 엘엘씨 Pde1 억제제로서의 치환된 푸라노피리미딘 화합물

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT95899A (pt) * 1989-11-17 1991-09-13 Glaxo Group Ltd Processo para a preparacao de derivados indole
WO1995027202A1 (fr) * 1994-03-30 1995-10-12 Ciba-Geigy Ag Methode de criblage a l'aide de la famille de recepteurs rzr
US5639780A (en) * 1995-05-22 1997-06-17 Merck Frosst Canada, Inc. N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
MX2007000791A (es) 2004-08-03 2007-03-23 Wyeth Corp Indazoles utiles en el tratamiento de enfermedades cardiovasculares.
WO2006034419A2 (fr) * 2004-09-21 2006-03-30 Athersys, Inc. Acides indole acetiques antagonistes du recepteur crth2 et ses utilisations
EP1828180A4 (fr) 2004-12-08 2010-09-15 Glaxosmithkline Llc 1h -pyrrolo[2,3-beta]pyridines
EP2181710A1 (fr) * 2008-10-28 2010-05-05 Phenex Pharmaceuticals AG Ligands pour la modulation de l'activité du récepteur gamma orphelin (NR1F3)
EP2459184A1 (fr) * 2009-07-31 2012-06-06 The Brigham and Women's Hospital, Inc. Modulation de l expression de sgk1 dans les cellules th17 pour moduler les réponses immunitaires médiées par th17
WO2011055270A1 (fr) * 2009-11-04 2011-05-12 Wyeth Llc Antagonistes des récepteurs crth2 à base d'indole
EP2487159A1 (fr) * 2011-02-11 2012-08-15 MSD Oss B.V. Inhibiteurs du RORgammaT
JP2014166961A (ja) * 2011-06-20 2014-09-11 Dainippon Sumitomo Pharma Co Ltd 新規インダゾール誘導体
WO2014026329A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'indazole et d'indole n-alkylés en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2014026327A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2014026330A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés 3-aminocycloalkyles en tant qu'inhibiteurs de rorgammat et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
WO2014028597A3 (fr) 2014-05-01
HUE045379T2 (hu) 2019-12-30
CN104822376A (zh) 2015-08-05
US20150191434A1 (en) 2015-07-09
CY1122272T1 (el) 2020-11-25
EP2884976A2 (fr) 2015-06-24
LT2884976T (lt) 2019-10-10
CA2881696A1 (fr) 2014-02-20
RS59364B1 (sr) 2019-11-29
PL2884976T3 (pl) 2020-02-28
US9487490B2 (en) 2016-11-08
HRP20191654T1 (hr) 2019-12-13
ME03579B (fr) 2020-07-20
BR112015003332A2 (pt) 2017-09-26
PT2884976T (pt) 2019-10-24
EP2884976A4 (fr) 2016-04-06
ES2749713T3 (es) 2020-03-23
KR20150041800A (ko) 2015-04-17
SI2884976T1 (sl) 2019-11-29
JP6232429B2 (ja) 2017-11-15
DK2884976T3 (da) 2019-09-23
JP2015526443A (ja) 2015-09-10
RU2015108898A (ru) 2016-10-10
WO2014026328A1 (fr) 2014-02-20
WO2014028597A2 (fr) 2014-02-20
AU2013302644A1 (en) 2015-03-05

Similar Documents

Publication Publication Date Title
EP2884976B1 (fr) Composés indazole et indole à substitution cyclohexyl et 3-cyclohexenyl comme inhibiteurs de ror-gamma-t et leur utilisation
EP2683693B1 (fr) Inhibiteurs de rorgammat
EP2884977B1 (fr) Composés indazole et indole n-alkylés utilisés en tant qu'inhibiteurs de rorgammat et utilisations de ceux-ci
EP2920149B1 (fr) Composés 3-aminocycloalkyl comme inhibiteurs de ror-gamma-t et leurs utilisations

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150212

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

A4 Supplementary search report drawn up and despatched

Effective date: 20160303

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 401/06 20060101ALI20160226BHEP

Ipc: C07D 403/06 20060101ALI20160226BHEP

Ipc: A61K 31/454 20060101ALI20160226BHEP

Ipc: C07D 209/26 20060101ALI20160226BHEP

Ipc: A61K 31/416 20060101AFI20160226BHEP

Ipc: A61K 31/496 20060101ALI20160226BHEP

Ipc: A61P 29/00 20060101ALI20160226BHEP

Ipc: A61K 31/5377 20060101ALI20160226BHEP

Ipc: C07D 231/56 20060101ALI20160226BHEP

Ipc: C07D 471/04 20060101ALI20160226BHEP

Ipc: A61P 37/00 20060101ALI20160226BHEP

17Q First examination report despatched

Effective date: 20170602

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20180601

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTC Intention to grant announced (deleted)
INTG Intention to grant announced

Effective date: 20181026

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602013058287

Country of ref document: DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1157378

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190815

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20191654T

Country of ref document: HR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20190919

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 2884976

Country of ref document: PT

Date of ref document: 20191024

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20191003

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20190913

Year of fee payment: 7

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: STOLMAR AND PARTNER INTELLECTUAL PROPERTY S.A., CH

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20190724

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20191029

Year of fee payment: 7

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20191654T

Country of ref document: HR

Payment date: 20191107

Year of fee payment: 7

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20191654

Country of ref document: HR

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E018232

Country of ref document: EE

Effective date: 20191010

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E045379

Country of ref document: HU

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 32404

Country of ref document: SK

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20190403041

Country of ref document: GR

Effective date: 20200122

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LT

Payment date: 20191104

Year of fee payment: 7

Ref country code: HU

Payment date: 20191104

Year of fee payment: 7

Ref country code: CZ

Payment date: 20191105

Year of fee payment: 7

Ref country code: RO

Payment date: 20191105

Year of fee payment: 7

Ref country code: NL

Payment date: 20191029

Year of fee payment: 7

Ref country code: NO

Payment date: 20191121

Year of fee payment: 7

Ref country code: BG

Payment date: 20191122

Year of fee payment: 7

Ref country code: SE

Payment date: 20191029

Year of fee payment: 7

Ref country code: FI

Payment date: 20191029

Year of fee payment: 7

Ref country code: PT

Payment date: 20191106

Year of fee payment: 7

Ref country code: SK

Payment date: 20191105

Year of fee payment: 7

Ref country code: MC

Payment date: 20191121

Year of fee payment: 7

Ref country code: CY

Payment date: 20191101

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20191108

Year of fee payment: 7

Ref country code: SI

Payment date: 20191105

Year of fee payment: 7

Ref country code: DK

Payment date: 20191029

Year of fee payment: 7

Ref country code: EE

Payment date: 20191119

Year of fee payment: 7

Ref country code: RS

Payment date: 20191108

Year of fee payment: 7

Ref country code: IS

Payment date: 20191118

Year of fee payment: 7

Ref country code: BE

Payment date: 20191029

Year of fee payment: 7

Ref country code: LV

Payment date: 20191120

Year of fee payment: 7

Ref country code: ES

Payment date: 20191030

Year of fee payment: 7

Ref country code: SM

Payment date: 20191119

Year of fee payment: 7

Ref country code: GR

Payment date: 20191030

Year of fee payment: 7

Ref country code: HR

Payment date: 20191107

Year of fee payment: 7

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2749713

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20200323

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20191105

Year of fee payment: 7

Ref country code: AT

Payment date: 20191030

Year of fee payment: 7

Ref country code: CH

Payment date: 20191125

Year of fee payment: 7

Ref country code: MT

Payment date: 20191128

Year of fee payment: 7

Ref country code: MK

Payment date: 20191105

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20191030

Year of fee payment: 7

Ref country code: AL

Payment date: 20191121

Year of fee payment: 7

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602013058287

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20200603

REG Reference to a national code

Ref country code: HU

Ref legal event code: HC9C

Owner name: MERCK SHARP & DOHME CORP., US

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20191654

Country of ref document: HR

Effective date: 20200814

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E018232

Country of ref document: EE

Effective date: 20200831

REG Reference to a national code

Ref country code: NO

Ref legal event code: MMEP

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20200831

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20200901

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 1157378

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200814

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 32404

Country of ref document: SK

Effective date: 20200814

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: RS

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: NO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210304

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200815

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20200831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210228

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200815

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20200814

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: SM

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210512

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210517

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200815

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200831

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20210811

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200901

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20220110

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200815

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602013058287

Country of ref document: DE

Owner name: MERCK SHARP & DOHME LLC, RAHWAY, US

Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, N.J., US

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20221013 AND 20221019

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 1157378

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190724

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20230712

Year of fee payment: 11

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200814

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230710

Year of fee payment: 11

Ref country code: DE

Payment date: 20230711

Year of fee payment: 11